We propose to synthesize multifunctional drug-loaded microbubbles for image-guided regional and systemic epigenetic therapies in cancer. The proposed research targets the following specific aims: (1) synthesis, characterization, and optimization of multifunctional drug-loaded microbubbles; (2) microbubble-assisted synergistic epigenetic therapies with ultrasound and fluorescence imaging guidance. The research is designed to verify the following major hypotheses: (1) microbubble-assisted regional epigenetic therapy in combination with PI3K/AKT signaling inhibition will significantly enhance the anti-cancer synergy; (2) systemic delivery of combinatory epigenetic therapies by tumor-targeting microbubbles will increase the therapeutic efficiency, reduce the therapeutic dose requirement, and minimize the systemic side effect. The proposed research paves the way toward an image-guided closed-loop schema for synergistic epigenetic therapies. The project is initiated by a team of researchers with multidisciplinary expertise in cancer detection, molecular imaging, cancer pharmaceutics, epigenetic therapy, drug delivery, microfabrication, and biomedical imaging. Clinical safety and efficacy have been considered at the early stage of the project to facilitate the future clinical translation from the benchtop to the bedside.